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Relationship: 2731
Title
Decrease, GLI1/2 target gene expression leads to Decrease, SHH second messenger production
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Antagonism of Smoothened receptor leading to orofacial clefting | adjacent | Low | Low | Arthur Author (send email) | Under development: Not open for comment. Do not cite | Under Development |
Decrease, GLI1/2 target gene expression leads to orofacial clefting | adjacent | Low | Low | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
Embryo | High |
Key Event Relationship Description
A network of reciprocal growth factor signaling between the epithelium and mesenchyme is required for proper growth and patterning of the early palatal shelves. This signaling is largely comprised of a network between bone morphogenic protein (BMP), Fibroblast growth factor (Fgf), and Sonic Hedgehog (SHH) (Zhang, Song et al. 2002, Rice, Spencer-Dene et al. 2004). Activation of the SHH pathway results in a downstream signaling cascade resulting in the relocation of GLI to the nucleus and subsequent gene transcription (Carballo, Honorato et al. 2018). This gene expression drives secondary messenger signaling for the pathway. Proper Msx1 activity in the mesenchyme is required for the expression of SHH in the overlying epithelium (Zhang, Song et al. 2002). Maintenance of SHH expression in the epithelium is believed to be dependent on Fgf10 expression in the mesenchyme and its’ signaling through Fgfr2b in the epithelium (Rice, Spencer-Dene et al. 2004).
Evidence Collection Strategy
Pubmed was used as the primary database for evidence collection. Searches are organized by the date and search terms used in the supplementary table. Search results were initially screened through review of the title and abstract for potential for data relating SHH signaling and SHH second messenger production. Each selected publication and its’ data were then examined to determine if support or lack thereof existed for this KER. Papers that did not show any data relating to this KER were discarded. The search terms used are organized below in Table 1.
Evidence Supporting this KER
Biological Plausibility
SHH signaling is well established to be essential for proper embryonic development in vertebrates including mice and humans. Activation of the pathway results in a downstream signaling cascade resulting in the relocation of GLI to the nucleus and subsequent gene transcription (Carballo, Honorato et al. 2018). SHH cross talks with other developmental pathways including FGF and BMP.
Empirical Evidence
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- In Osr2-IresCre;Smoc/c (SHH pathway inactive) mutant mice Fgf10 mRNA was found to be significantly reduced in the anterior palatal mesenchyme. The expression of Fgf10 correlated with a downregulation of PTCH1 (Lan and Jiang 2009).
- To determine if SHH can induce Fgf10, SHH overexpressing cells were implanted in the anterior region of the wing bud of chick embryos. By 27 hours, the expression of Fgf10 had significantly increased and expanded from the anterior mesenchyme to the bifurcating wing bud (Ohuchi, Nakagawa et al. 1997).
- To investigate whether MSX-1 is in the same pathway as Fgf10, MSX-1 expression was examined in Fgf10-/- mice and Fgf10 expression was examined in Msx-1-/- mice. No change in expression was found and it is concluded that MSX-1 is not a downstream target of Fgf10 (Alappat, Zhang et al. 2005).
- SHH expression is reduced in the palatal epithelium of both Fgf10-/- and Fgfr2b -/- mutants. Exogenous Fgf10 induced SHH in WT palatal epithelium (Rice, Spencer-Dene et al. 2004).
- BMP2 and BMP4 is downregulated in the anterior palate of Osr2-IresCre;Smoc/c (SHH pathway inactive) mutant mice (Lan and Jiang 2009).
- Upregulation of mesenchymal BMP4 by SHH via Foxf1 or Foxl1 (Katoh and Katoh 2009).
Uncertainties and Inconsistencies
The relationships and feedback/feedforward loops that exist between SHH and its’ secondary messengers primary Fgf10 and BMP4 is not well understood. Some evidence exists that expression of both Fgf10 and BMP4 correlates with that of SHH. The state of evidence is lacking and no dose response data was found.
Known modulating factors
Quantitative Understanding of the Linkage
The quantitative understanding of this KER is low. There is a lack of specific experimental evidence that has investigated the relationship. More studies are needed to investigate how dose response, time scale, etc for this relationship.
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between a decrease in shh target gene expression and a decrease in secondary messenger production has been shown in mouse models. The relationship is biologically plausible in human, but to date no specific experiments have addressed this question. The SHH pathway is well understood to be fundamental to proper embryonic development and that aberrant SHH signaling during embryonic development can cause birth defects including orofacial clefts (OFCs). For this reason, this KER is applicable to the embryonic stage with a high level of confidence.
References
Alappat, S. R., Z. Zhang, K. Suzuki, X. Zhang, H. Liu, R. Jiang, G. Yamada and Y. Chen (2005). "The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice." Dev Biol 277(1): 102-113.
Carballo, G. B., J. R. Honorato, G. P. F. de Lopes and T. C. L. d. S. e. Spohr (2018). "A highlight on Sonic hedgehog pathway." Cell Communication and Signaling 16(1): 11.
Cobourne, M. T. and J. B. Green (2012). "Hedgehog signalling in development of the secondary palate." Front Oral Biol 16: 52-59.
Katoh, Y. and M. Katoh (2009). "Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation." Curr Mol Med 9(7): 873-886.
LaBonne, C. and M. Bronner-Fraser (1999). "Molecular mechanisms of neural crest formation." Annu Rev Cell Dev Biol 15: 81-112.
Lan, Y. and R. Jiang (2009). "Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth." Development 136(8): 1387-1396.
Ohuchi, H., T. Nakagawa, A. Yamamoto, A. Araga, T. Ohata, Y. Ishimaru, H. Yoshioka, T. Kuwana, T. Nohno, M. Yamasaki, N. Itoh and S. Noji (1997). "The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor." Development 124(11): 2235-2244.
Rice, R., B. Spencer-Dene, E. C. Connor, A. Gritli-Linde, A. P. McMahon, C. Dickson, I. Thesleff and D. P. Rice (2004). "Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate." J Clin Invest 113(12): 1692-1700.
Zhang, Y., X. Zhao, Y. Hu, T. St Amand, M. Zhang, R. Ramamurthy, M. Qiu and Y. Chen (1999). "Msx1 is required for the induction of Patched by Sonic hedgehog in the mammalian tooth germ." Dev Dyn 215(1): 45-53.
Zhang, Z., Y. Song, X. Zhao, X. Zhang, C. Fermin and Y. Chen (2002). "Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis." Development 129(17): 4135-4146.